ISD: Inferential Structure Determination

Structure determination is generally done by minimisation. Experimental data
(e.g. NOE peak intensities) are converted to constraints (e.g. distance bounds),
combined with a molecular force field, and minimised. In practice you need to
estimate (guess) parameters like calibration constants for peak intensities,
distance cut-offs, correlation times, and the weighting constants for different
data points. The final result is a (family of) structure(s) , but there is no
reliable way of determining the uncertainty of the coordinates.

ISD (Inferential Structure Determination) uses Bayesian statistics to calculate
the distribution of probable results given the input information. The program
randomly samples different structures and calculates the measurement results
that each would have produced. The difference between the calculated and
measured results determines how likely each structure is, and the total set of
sampled structures gives you the distribution of likely structures given the
input data and prior information. There is no need to estimate calibration
constants, data weightings etc. beforehand - the program can sample randomly
over different values and find the likely values just like it finds the likely
coordinates for the structures. Ultimately the program gives you a family of
structures with an uncertainty estimate for all coordinates, all calibration
constants. The data weightings calculated for data points tell you how well each
point fits and so gives you a built-in validation of the data.

Random sampling over large numbers of structures is very computationally
demanding. ISD uses Markov Chain Monte Carlo sampling with replica exchange,
simulating many structures in parallel at different temperatures. The program
has been set up to run on clusters to provide faster results.

The graphical interface to ISD

ISD Benefits

NMR structures with uncertainties ('error bars') on the coordinates

No free parameters

No need to set calibrations scaling constants etc. - ISD estimates them in the calculation